21-sulfinyl steroids

ABSTRACT

NOVEL 21-SULFINYL STEROIDS, HAVING UTILITY AS ANTI-INFLAMMATORY AGENTS, ARE DISCLOSED.

United States Patent 3,803,133 ZI-SULFINYL STEROIDS B. Richard Vogt,North Brunswick, N.J., assignor to E. R. Squibb 8: Sons, Inc.,Princeton, NJ. No Drawing. Filed Dec. 15, 1972, Ser. No. 315,701 Int.Cl. C07c 173/00 US. Cl. 260-23955 D 7 Claims ABSTRACT OF THE DISCLOSURENovel 2l-sulfinyl steroids, having utility as anti-inflammatory agents,are disclosed.

SUMMARY OF THE INVENTION Novel 21-sulfinyl steroids having the followingformula:

Alternatively, R and K, may together form a cyclized dioxolo group, i.e.

or a cyclized oxazole group, i.e.

N=CR| 3,803,133 Patented Apr. 9, 1974 (III) Throughout thespecification, the symbol R represents lower alkyl, cycloalkyl, aryl,and aralkyl.

DETAILED DESCRIPTION OF THE INVENTION The compounds of Formula I arephysiologically active substances which possess glucocorticoid andanti-inflammatory activity and hence can be used in lieu of knowngucocorticoids in the treatment of rheumatoid arthritis, for whichpurpose they can be administered in the same manner as hydrocortisone,for example, the dosage being adjusted for the relative potency of theparticular steroid. In addition, the compounds of this invention can beused topically in leu of known glucocorticoids in the treatment of skinconditions such as dermatitis, sunburn, neurodermatitis, eczema, andanogenital pruritus.

When given orally, the compounds of this invention may be used in adosage range of 0.1 to 200 milligrams,

preferably 0.3 to milligrams. If administered topically,

3 the compounds of this invention may be used in the range of .01 to5.0% by weight, preferably .05 to 2.0% by weight, in a conventionalcream or lotion.

The expression lower alkyl referes to those alkyl groups having from 1to 6 carbon atoms, and includes both straight and branched chains, e.g.,methyl, ethyl, propyl, isopropyl, t-butyl, etc.

The expression cycloalky refers to monovalent saturated hydrocarbonrings containing from 3 to 7 carbon atoms, e.g., cyclopropyl,cyclobutyl, etc.

The expression aryl refers to monocyclic carbocyclic aromatic groupsthat may either be unsubstituted or substituted with halogen, loweralkoxy (i.e. R wherein R is lower alkyl as defined above) or lower alkylgroups (as defined above) e.g. phenyl, ethoxyphenyl, propylphenyl,chlorophenyl, tolyl, etc.

The expression aralkyl refers to lower alkyl groups (as defined above)substituted with an aryl group (as defined above) e.g. benzyl,phenethyl, etc.

The term halogen refers to F, Cl, Br and I (Cl and Br are preferred).

The novel 21-sulfinyl steroids of Formula I are steroids of the A-pregnene series (including the pregnadiene, pregnatriene, andpregnatetraene series).

The starting materials for making the compounds of this invention are:

and

(VII) Steroids of this type are known (see, for example, US. Pat. No.3,048,581 to Fried et al. and British Pat. No. 869,511).

The steroids of Formula I can be prepared by several different methods.One method of synthesis involves the selective oxidation of aZI-substituted thio steroid with an appropriate selective oxidizingagent:

The oxidizing agent may be any compound capable of preferentiallyoxidizing a divalent sulfur atom of the type present in Formula II tothe corresponding sulfoxide oxidation state in the presence of hydroxygroups, keto groups and/or carbon-carbon double bonds. Iodosobenzenediacetate, N-bromoand N-chloro-succinimide, iodobenzene dichloride andsodium metaperiodate are exemplary of suitable oxidizing agents. Sodiummetaperiodate is preferred.

The oxidation reaction is carried out in a solvent which is essentiallyor completely inert to the reactants and provides some degree ofsolution for both the starting steroid and oxidizing agent. When sodiummetaperiodate is used as the oxidizing agent, low molecular weightalcohols (e.g. methanol) are preferable solvents. Reaction of the2l-substituted thio steroid with the oxidizing agent may be carried outat temperatures ranging from about 50 C. to about C. preferably within atemperature range of -15 C. to +40 C. for a period of time ranging fromabout 12 hours to 7 days, preferably from 1 to 4 days. Isolation of the2l-sulfinyl steroid may be accomplished by pouring the reaction mixtureinto water (if a water miscible solvent is used), filtering oil thedesired product and drying.

Preparation of the novel 21-substituted thio steroids of Formula II maybe accomplished by reacting alkali metal salts of mercaptans (MSRwherein M is an alkali metal, preferably sodium or potassium) withsteroids of Formula V:

An alternative method for preparing the ZI-substituted thio steroids ofFormula II is to react an alkali metal salt of a mercaptan (MSR withsteroids of Formula W:

Instead of iodine in the C-21 position, other halogens may be used;however, iodine is preferred.

The conversion of the steroids of either Formula V or Formula VI to theZl-Substituted thio steroids of Formula II is carried out in a suitablenonreactive, polar solvent such as methanol, acetonitrile ordimethylformamide. The reaction takes from 12 hours to 7 days,preferably from 1 to 3 days at from 0 C. to C., preferably from 30 C. to60 C. The starting steroid is reacted. with from 1 to 6, preferably 1 to3 molar equivalents of the alkali metal salt derivative of theappropriate mercaptan (i.e., HSR Upon completion, the reaction isneutralized (if necessary), poured into water, and the ZI-substitutedthio steroid of Formula II is. filmed otf and dried.

Another alternative for preparing -21 alkylthio steroids of Formula Hinvolves the selective alkylation of the corresponding C-21 mercaptosteroid of Formula III.

Base 0 alkylatlng agent The alkylating agent may be represented by theformula R X wherein X may be or a halogen. The 0-21 mercapto steroid ofFormula III is reacted with a slight excess of a base such as sodiumhydride in a non-reactive polar solvent such as 1,2- dimethoxyethane forabout 15 minutes to 24 hours, preferably for 1 to 3 hours at from 0 C.to 5-1-80 0., preferably from +30 C. to +50 C. The reaction is thentreated with a slight excess of the appropriate alkylating agent (R Xfor about 30 minutes to 48 hours, preferably 3 to 24 hours at from +50C. to +100 0., preferably from +25 C. to +80 C. Evaporation of thesolvent gives the 21-substituted thio steroid of Formula II.

The 0-21 sulfonates of Formula V can be prepared by reacting thecorresponding 0-21 hydroxy steroid of Formula VII with about 1 molarequivalent of a sulfonyl halide, i.e.

O Rr Y where Y is chlorine or bromine.

The reaction is carried out in an inert anhydrous solvent containing anappropriate hydrogen acceptor (e.g. a' tertiary amine such astriethylamine or a basic heterocyclic amine such as pyridine).

An explained above, reaction of the 0-21 hydroxy steroid of Formula VIIwith the sulfonyl halide may be run in an inert anhydrous solvent.Alternatively, the reaction can be run in a liquid tertiary amine orbasic heterocyclic amine hydrogen acceptor. The reaction time can befrom a few hours to several days, preferably from 12 to 24 hours, whilethe reaction temperature can be from C. to +40 0., preferably between 50C. and 10 0. Upon completion the reaction is poured into could water andthe steroid of Formula V is filtered off and dried.

} The 0-21 iodo steroids of Formula VI can be obtained using well knownprocedures (see I Am. Chem. Soc., 80, 250 (1958) and 81, 439 (1959); J.Org. Chem., 25, 1966 (1960) One general procedure for the preparation ofa 0-21 iodo steroid of Formula VI involves starting with an appropriatesteroid of the following formula (i.e. a steroid unsubstituted in the0-21 position);

(VIII) The steroid of Formula VIII is reacted with a mixture of calciumoxide, iodine, and a free radical initiator, preferablya,a-azabisisobutyronitrile, in a suitable solvent system such astetrahydrofurammethanol.

Is, 0110 free radical After a period of time of from about 30 minutes to24 hours, preferably from 1 to 4 hours at from 30 C. to +50 C.,preferably +10 C. to +30 C., the reaction is diluted with a suitableorganic solvent, such as methylene chloride, washed with an aqueoussolution of a compound capable of removing excess iodine, such as sodiumthiosulfate, and the organic solvent evaporated to 'give the C-21 iodosteroid of Formula VI.

Another procedure for the preparation of C-21 iodo steroid of Formula VIinvolves reacting a -21 sulfonate steriod of Formula V with an alkalimetal iodide salt, preferably sodium or potassium, in a polar,non-reactive solvent such as acetone or a lower molecular weightalcohol.

The reaction time is from about 1 hour to 5 days, preferably 6 hours to2 days at from -10 C. to +80 C., preferably from +20 C. to +50 C. Uponcompletion, the reaction is treated with a low molecular weightcarboXylic acid (e.g. acetic acid) equivalent to the amount of baseused, and poured into water. The product is filtered off and dried.

An alternative method for the preparation of the 21- mercapto steroidsof Formula III involves the reaction of a C-21 substituted steroid ofFormula V or Formula VI (or Formula VI with a halogen other than iodinein the C-21 position) with an alkali metal (preferably sodium orpotassium) salt of hydrogen sulfide (i.e. MSH) in a polar solvent suchas dimethyl formamide or a lower molecular weight alcohol such asethanol.

alkali metal iodide 25 ---b salt The reaction time may be from about 30minutes to 48 hours, preferably from 1 to 24 hours at from 20 C. to +100C. preferably from +10 C. to 80 C. The solvent is then evaporated, theresidue stirred with water and the 0-21 iodo steroid is filtered off anddried.

Several methods are available for the preparation of ZI-mercaptosteroids of Formula III. One method involves the reaction of a C-21acylthio steroid of Formula IV with about 1 to 5, preferably 1.1 to 3,molecular equivalents of an alkali metal (preferably sodium orpotassium) salt of a lower molecular weight alcohol (e.g. sodiummethoxide) or an alkali metal carbonate (e.g. potassium carbonate) in awet, non-reactive polar solvent such as the corresponding alcohol (e.g.methanol) or dimethyl sulfoxide.

In the second equation, other halogens may be substituted for iodine inthe steroid of Formula VI. The reaction time is from about 15 minutes to4 days, preferably 30 minutes to 2 days, at from +25 C. to +200 C.,preferably from C. to +150 C. Upon completion, the reaction isconcentrated to a small volume, cooled, neutralized with one equivalentof a strong acid (e.g. hydrochloric acid), poured into five volumes ofwater, and the C-21 mercapto steroid of Formula III is filtered off anddried.

The 21-acylthio steroids of Formula IV can be prepared by reacting asteroid of Formula V or Formula VI (or Formula VI with a halogen otherthan iodine in the C-21 position) with about 1 to 5, preefrably l to 3,molecular equivalents of an alkali metal (preferably potassium) salt ofa thio carboxylic acid of formula (III) in a non-reactive polar solventsuch as acetone or dimethylformamide.

In the second equation, other halogens may be substituted for iodine inthe steroid of Formula VI. The reaction time is from about 1 hour to 4days, preferably from 3 hours to 2 days, at from C. to +100 C.,preferably from C. to +70 C. The solvent is evaporated, the residuestirred with water, and the product filtered off and dried.

10 The diagram below is a summary of the above described processes forproducing the novel compounds of this invention. In the diagram, thesymbol K represents:

In the following examples all reactions are run under an inertatmosphere (e.g. argon), at room temperature, using anhydrous solventsunless otherwise indicated; in addition, reactions which are heated aresubsequently cooled to room temperature for work-up. Steroids named as9-halo refer to the 9a-halo.

EXAMPLE 1 9-fluoro 115,16d,17,21 tetrahydroxypregna-l,4-diene-3,20-dione, 21-p-toluenesulfonate, cyclic 16,17-acetal with acetone To 2.9g. of 9-fiuoro-115,16a,17,2l-tetrahydroxypregna- 1,4diene-3,20dione,cyclic 16,17-acetal with acetone dissolved in 30 ml. of dry pyridine at56 C. is added a 0 C. solution of 1.8 g. of p-toluenesulfonyl chloridein 18 ml. dry methylene chloride. The reaction is stirred at 30 C. for 2hours and then at -5 C. for 96 hours. The reaction is poured intochloroform and washed consecutively with water, dilute hydrochloricacid, dilute aqueous sodium carbonate and water. The chloroform solutionis dried with sodium sulfate and the solvent 5 evaporated to give thecrude title compound. After stirring with water, the product is filteredoff, dried and re crystallized from a mixture of acetone-hexane, M.P. is

EXAMPLES 21 8 Following the procedure of Example 1 but substituting thesteroids in Column I below for 9-fluoro-1 l B,16a,17,21-tetrahydroxypregna-1,4-diene 3,20 dione, cyclic 16,17- acetal withacetone in Example -1, the corresponding 5 steroid tosylates indicatedin Column II are obtained:

16,-methylpregna-1,4- diene3,20-dione.

8 9-iiuoro-11fl,17,21-trihydroxy- 16a,-methylpregna-l,4-diene3,20-dione.

12.....- 9,1lB,-dichloro-66-fluoro-16,

17,21-trihydroxypregna- 1,4-dlene-3,20-dione, cyclic 16,17acetal withacetone.

13... 11fl,16a,17,21-tetrahydroxypregna-1,4'diene-3,20 dione, cyclic16,17-amta1 with acetone.

14".-- 115,17 21-trlhydi'oXy-16 met ylenepregna-1,4-dlene- 3,20-dione.

16..... 9-fluoro-l1fl,17,21-trihydr0xy- 16-methylenepregna-1,4-diene-3,20-dione.

ione. 18"... 9-fluoro-1lfl,l6a,17,21-tetrahydroxypregna-L-tdiene- 3,20-dione, Iii-acetate.

16a,-methylpregna-1,4-diene 3,20-dione, 21-p-toluenesulionate. 6a,9iifluoro-11fl,l7a,21-trihydmxy-16a,-methylpregna- 1,4-diene-3,20dione,2l-ptoluenesulionate. 6a,9-difluoro-11B,16a,l7,2i-

tetrahydroxypregna-M diene-3,20-dione, 21-ptoluenesulionate, cyclic16,17- aeetal with acetone. 6a-fluoro-11B,2l-dihydroxy-16e:-

methyipregna-1,4 dime-3,20- dione, 21-ptoluenesulionate.9,l1fi-dicl1loro-6B-fluoro-l6a,l7,21-

trlhydroxypregna-Li-diene- 3,20-dione, 2l-p-toluene sulfonate, cyclic16,17-acetal with acetone.11B,16a,i7,21-tetrahydroxypregna-IA'dieneSJO-dione, 2bp-toluenm1lfonate,cyclic 16, i7-acetal with acetone. 1lfl,17,21-trihydroXy-16-methylene-pregna-htdlene' 3,20-dione, 21-p-tcluene- EXAMPLES 19 AND 20fonyl chloride in Example 1, sulfonates indicated in Column II areobtained.

the corresponding steroid Column I Methanesulionyl bromidedr0Xypregna-1,4-diene-3,20-

dione, 21-cyelopentylsulionatc,

gyclic 16,17-acetal with aceone.

EXAMPLE 21 9-fluoro-1 1B,16a,17-trihydroxy-21- (methylthio) -pregna-l,4-diene-3,20-dione, cyclic 16,17-acetal with acetone 5.0 g. of9-fluoro-115,160,17,21-tetrahydroxy-pregna- 1,4-diene-3,20-dione,21-p-t0luenesulfonate, cyclic 16,17- acetal with acetone and 2.1 g. ofsodium methyl mercaptide in ml. of dry methanol are refluxed under argonat room temperature for 60 hours. The reaction is acidified with 3.0 ml.of glacial acetic acid, diluted with 75 ml. water and the aqueoussolution concentrated to a minimal volume. The crude productprecipitated out, is filtered off, washed with water and dried. Afterrecrystallization from an acetone-petroleum ether mixture, the producthas EXAMPLES 22-38 Ex. Column I Column II 22---. 9-fluoro11fl, 17, 21-9-fluoro-118. 16o: 17-trihydroxytetrahydroxy-pregnaA-ene- 21(methylthio3 pregnai-ene- 3,20-dione-2l-p-toluenesulionate, cyclic 16,17-acetal with acetone.

23..... 9-fluoro11fi, 16a, 17, 21-

tetrah droxypregna-1,4- diene ,ZtHiione, 21-ptoluenesultonate, cyclic16,17-acetal with acetophenone (B-methyl).

24.--- 9-fluoro-11p,16,l7,21-tetrahydroxypregno-Ltdlenc- 3,20-dione,21-p-toluenesulinnate, cyclic 16,17-acetal with acetaidehyde (trmethyl).

25- 9fluoro-1lfl,16a,17,2I-tetrahydroxypregna-1,4-diene 3,20dione,2l-p-toluenesultonate, c 0110 16,17'ocetal with eye ohexanone.

26---- 11fl,l7,21-trihydroxy-6,l6-

dimethyl-1,4,6,l5-pregnatetraenes'modionefll-ptoluenesulionate.

toluenesulionate.

29---- 6a,9-difluoro-llfl,l7a,21-

trihydroxy-lGa-methylpregna-1,4-diene-3,20-dione, 2l-p-toluenesulionate.

32-.-- 9,11fl-dichloro-6B-fluoro-l6a,

l7,2l-trihydroxypregna-l,4- dieneSJO-dione, 21-p toiuenesuifonate,cyclic 16,17-acetal with acetone.

33- 11fl,16a,17,21-tetrahydroxypregna-1,4diene-3,20-dione,2l-p-toluenesuli'onate, cyclic 16,17-acetal with acetone.

34.--- 1lB,17,2l-trihydroxy-16- methylenepregna-l,4-diene- 3,20-dione,2l-p-to1uenesulionate.

3,20diene, cyclic 16,l7-acetal with acetone.

9-fluoro-11B, 16a. 17-trlhydroxy- 21 (methylthios pregna-l,4- dienei,20-dione, c clic 16,17- acetal with acetop enone (B-methyl).

9-fluoro11fl,16a,17-trihydroxy- 21(methylthio)pregna-l,4-dicne-3,20-dione, cyclic 16,17- acetal with cyclohexanone.

11B,17dihydroxy-6,16-dimethyi- 21(methylthio)-l,4,6,l5-pregnatetraene-3,20-dione.

9,iifl-dichloro-GBJiuoro-IMJI- dihydroxy-21-(methylthio)-pregna-l,4diene3,20-dione, cyclic 16.17-acetal with acetone.

11fl,16cr,17-ti'ihydr0!y-21- (methylthio)-pregna-l,4- diene-Zi,20-dione,cyclic 16,17- acetal with acetone.

11B,l7-dihydroxy-l6-methylene- ZI-(methylthio) pregna-l ,4-diene-3,20-dione.

EXAMPLES 39-45 Followingthe procedures of Example 21, but substitutingthe mercaptides in Column I below for sodium methyl mercaptide inExample 21, the corresponding 21-substituted thio steroids indicated inColumn H are obtained.

42-... Sodium thiophenolate 1,4-d1ene'3,20-dione,cyclic 16, l7-acetalwith acetone. 44.... Potassium-p-methoxy- Qa-fluoro-llfi,l6a.17-trihydroxythlphenolate. 21-(p-methoxypl1enylthio)pregna-1,4-diene3,2 -dione,

cyclic 16,17-eoetal with acetone 9a-fluoro-11 ,lfia, 17-trlhydroxy-2l-(p-met ylphenylthio) pregna-1,4 ilene-3,20-d.ione, cyclic16,17-acetal with acetone.

45 Sodium p-methylthlophenolate.

EXAMPLES 46 AND 47 9fluoro- 1 15,1601, l7-trihydroxy-21- (methylthio)-pregnal,4-diene-3,20-dione, cyclic 16,17-acetal with acetone Followingthe procedure of Example 21 but substituting the 2l-sulfonyl steroids inColumn I below for 9-fluoro- 11 B,16a,17 ,21-tetrahydroxypregna 1,4diene-3,20-dione, 2l-p-toluenesulfonate, cyclic 16,17-acetal withacetone in Example 21, gives the title compound.

Example: Column ii 46 9-fluoro 11,6,l6a,17,21 tetrahydroxypregna 1,4diene- 3,20-dione, 21 methanesulfonate, cyclic 16,17 acetal withacetone. 47 9 fluoro llfl,l6a,l7,2l-tetrahydroxypregna 1,4 diene 3,20dione, 21-cyclopentylsulfonate, cyclic 16,17-acetal with acetone.

EXAMPLE 48 9-fluoro- 1 15,16, 17-trihydroxy-21-(methylthio)-pregnal,4diene-3,20-dione, cyclic 16,17-acetal with acetone Followingthe procedure of Example 21 but substituting9-fiuoro-1lfl,l6a,l7-trihydroxy 21 iodopregna-l,4- diene-3,20-dione,cyclic 16,17-acetal with acetone for 9-fluoro-l1B,l6a,17,21-tetrahydroxypregna 1,4-diene-3,20- dione,21-p-toluenesulfonate, cyclic 16,17-acetal with acetone in Example 21gives 9-fluoro-llB,l6a,17-trihydroxy- 21-(methylthio)pregna-l,4-diene-3,20-dione, cyclic 16,17- acetal withacetone.

EXAMPLE 49 9 fluoro 11B,16a,17 trihydroxy-Zl-(methylsulfinyl)- pregna1,4 diene 3,20 dione, cyclic 16,17-acetal with acetone Method A: 2.0 g.of 9-fluoro-1lp,16a,17-trihydroxy-2l-(methylthio)pregna-1,4-diene-3,20-dione, cyclic 16,17- acetal withacetone and 0.92 g. of sodium metaperiodate in 400 ml. of methanol isstirred at 5 C. for five days. An additional 0.92 g. of sodiummetaperiodate is added at the end of the first and fourth day. Thesolvent is then evaporated. The crude product is dissolved in 400 ml.chloroform, washed with water, dried and chromatographed on a 20 g.Florisil column. 300 ml. of chloroform eluant is discarded. The columnis then eluted with 500 ml. ethyl acetate followed by 400 ml. acetone.These fractions are combined and the solvents evaporated to give theproduct. After recrystallization from methylene chloride-petroleumether, the product has a M.P.'=234- 236 C.

Method B: To 4.64 g. of 9-fiuoro-llt9,l6a,l7-trihydroxy-2l-(methylthio)pregna 1,4 diene-3,20-dione, cyclic 16,17-acetal with acetone in 800 ml.of methanol at 5 (ice water-salt bath cooling) is added, portionwise,1.33 g. of N-chlorosuccinimide at such a rate that the inernaltemperature of the reaction does not exceed 10 C. After stirring at 5for two days, the solvent is evaporated. The residue is dissolved inchloroform and washed successively with cooled, dilute aqueous sodiumhydroxide and then water.

The Organic phase is then dried, filtered and the solvent evaporated togive the title compound.

Method C: 4.64 g. of 9-fluoro-1 lB,16a,17-trihydroxy-21-(methylthio)-pregna-1,4-diene-3,20-dione, cyclic 16,17- acetal withacetone and 3.22 g. of iodosobenzene diacetate in ml. glacial aceticacid are refluxed for 4 hours. After standing for 16 hours at roomtemperature, the re action is filtered, heated to near its boiling pointand diluted with 450 ml. hot water. After standing at room temperatureovernight, the reaction is concentrated to ca. 200 ml., cooled to roomtemperature and the title compound filtered oif.

Method D: To 4.64 g. of 9fluoro-11p,16a,17-trihydroxy-21-(methylthio)pregna 1,4 diene-3,20-dione, cyclic 16,17-acetal with acetone in 200 ml.of 10% (V/ V) aqueous pyridine at 20 C., is added, dropwise, withstirring, 2.75 g. of iodobenzene dichloride in anhydrous pyridine.Direct sunlight is avoided. After ten hours, the reaction is dilutedwith chloroform and washed successively with dilute aqueous sulfuricacid and then water. After drying, the organic phase is evaporated togive the title compound.

EXAMPLES 50-66 Column II aeetal with acetone. acetal with acetone.

51-.-- B-fluoro-llfl,l6a,l7trlhydroxy- Q-fluoro-llB,16a,17-trihydroxy-2l-(methylthlo)-pregna-1,4- 2l-(methylsulfinyl)pregna-1,4dlene-3,20-dione, cyclic diene-3,20-dione, cyclic 16,17- 16,l7-acetalwith acetophe acetal with acetophenone (13- none (Q-methyl). methyl)diene4i,20-dione, cyclic diene-3,20-dlone, cyclic 16,17-16,17-acetalw1th acetalde acetal with acetaldehyde (w hyde (ct-methyl).

diene-3,2odlone, cyclic diene-3,2(Hiione, cyclic 16,17- llgggacggal withcycloacetal with cyclohexanone.

17 sium thioacetate in Example 74, the corresponding 21- acylthiosteroids indicated in Column 11 are obtained.

Ex. Column I Column II 92.--. Sodium thlohexanoateQ-fluoro-llfl,16a,17-trihydroxy- 21-mercapt0pregna-1,-diene- 3,20-dione,2l-hexanoate, cyclic 16,17-acetal with acetone.

9-fluoro-11B,16a,17-trihydroxy- 2Lmcrcaptopregna-1,4dicne- 3,20-dine,2l-benzoate, cyclic 16,17-acetal with acetone.

Q-fiuarc-115,160;,17-trihydroxy- .Zl-mercaptopregna-lA-diene-3,20-dione, 21-(p-chlorobenzoate), cyclic 16,17-acetal with acetone.

Q-fluorodlfldfia,17-trihydroxy- 21-mercapt0pregna-1,tdiene- 3,2041ione,2l-(p-methoxybenzoate), cyclic 16,17-acetal with acetone.

9-fiuoro-11fl,16a,17-trihydroxy- 21-mercaptopregna-1,4-diene-3,20-dione, 21-(p-methylbenzoate), cyclic 16,17-acetal with acetone.

EXAMPLE 97 EXAMPLE 98 9-fluoro- 1 15,164, 17-trihydroxy-2I-mercaptopregna-l ,4- diene-3,20-dione, cyclic 16,17-acetal withacetone Method A: 4.0 g. of 9-fluoro-1lB,16a,17-trihydroxy-21-mercaptopregna-1,4diene-3,20-dione, 21 acetate, cyclic 16,17-acetal withacetone and 0.62 g. of sodium methoxide in 115 ml. dry methanol arestirred for four days at room temperature. After acidifying with 3.3 ml.glacial acetic acid, the product is filtered off, washed with cold waterand dried. Several recrystallizations from a mixture of di methylformamide and methanol give a product with a M.P. of 315316 C.

Method B through F: Following the procedure of Method A, butsubstituting the bases in Column 1 below and the sol-"vents in Column IIbelow for sodium methoxide and for methanol, respectively, in Method Athe title compound is obtained.

93.... Thiobenzoic acid, potassium salt.

94.-.. p-Chloro-thiobenzoic acid, potassium salt.

95--.. p-Methoxythiohenzolc acid, potassium salt.

Method Column 1 Column II B Sodium ethoxide Ethanol.

. Potamium ethoxide- Do Potassium i-propoxide. I Isopropanol. Potassiumbicarbonate 5% aqueous methanol.

Potassium carbonate Do.

EXAMPLES 99-115 Following the procedure of Example 98 but substitutingthe 2l-acetylthio steroids in Column 1 below for9u-fluoro-11fi,16a,17-trihydroxy 21 mercaptopregna-1,4-diene-3,20-dione, ZI-acetate, cyclic 16,17-acetal with acetone inExample 98, the corresponding 21-mercapt0 steroids indicated in Column11 are obtained.

cyclic 16,17-acetal with acewith acetophenone (Li-methyl). tophenonei-methyl) 2l-mercapto pregna-1,4- 21-mercapto pregna-1,4-diene diene-3,20'di0ne, ZI-acetate, 3,20dione, cyclic 16 17-aeetal cyclic 16,17-acetalwith with acetaldehyde (at-methyl). eceta1dehyde(a-methyl).

TABLE- Continued Ex. Column I Column II 102.Q-fluoro-l1fi,16a,17-trihydroxy- 9-fluoro-11B,16a,17-trlhydroxy-ZI-mercapto pregna-1,4- 21-mercapto pregna-1,4dienediene-3,20dione,2l-acetate, 3,20dione,cyclic 16,17-acetal cyclic16,17-acetal with cywith cyclohexanone. clohexanone.

103... 116,17-dihydroxy-21-mercapto- 1119,17-dihydroxy-21-mercapto-6,16-dimethyl-1,4,6,15- 6,16-dimethyl-11,6,15-pregnapregnatetraene-iiflo dione, tetraene-3,20-d10ne.21-acetate.

104....9-iluoro- B,17-dihydroxy-21- 9-fluoro-1lB-17-dlhydroxy-21-mercapto-ltifl-methyl mercapto-lGfi-methylpregnapregna-1,4-d.iene-3,20-dione, 1,4-diene3,20-dlone. 21-acetatc.

9-fiuoro-11l3,17-dihydroxy-21-9-fiuoro-1lBJ7-dihydroxy-2lmercapto-ltia-methyl mercapto-lGa-methylpregnapregua-LkdienetflO-dione, 1,4-diene-3,20-d1one. 21-acetate.

106- 6a,94iifluoro-11fl,17a6a,9-difluoro-1lBJ7a-dihydroxyhydroxy-21-mercapto-l6w21-mercapto-16a-methy1 methyl pregua-lA'diene-Ii,pregna-LkdienetSiO-dione. 20-d1one, 21-acetate.

107--- 6a,9-difluoro-115,16a,17-trl- 6a,9-difll10r0-11B,16a,17-trihydroxy-21-mercapto hydroxy-21-mercaptopet-gnapregna-1,4-diene-3,20-dione, 1,441ieue-3,20'dlone, cyclic 16,16,17-acetal with acetone. 17acetal with acetone.

108. da-fluoro-ll/S-hydroxy-Zl- 6a-fluoro-11B-hydroxy-21-mercapto-lfia-methylmercapto-ma-methylpregnapregna-1,4-diene-3,20dione,1,4'diene-3,?x)dione. zl-acetate.

109..- 9,11 oichlaro-fiflhuoro-ma, 9,11B-dichloro6B-iluoro 16 17-17-dihydroxy-21-mercapto dihydroxy-Zl-mercapto pregna-lA'diene-il, "one,pregna-1,4-diene-3,20-dione, 2l-acetate, cyclic 16,17- cyclic16,17-acetal with acetal with acetone. acetone.

110--- 11B,16a,17-trihydroxy-21- 115,16a,17-trihydroxy-21-mermercaptopregua-1,4-dienecapto pregna-1,4-diene-3,20- 3,20-dione,21acetate,cyclic dione, cyclic 16,17-acetal with 16, 17-acetal with acetone.acetone.

111--- 116,17-dihydroxy-21-mer- 115,17-dihydroxy-21-mercaptwcapto-lG-methylene pregnalit-methylene pregna-1,4 lA-iigge-SflO-dione,21- diene-3,20-dione. ace a 112... 9-fluoroF11B-hydroxy-21-mer-9-fluoro1118-hydroxy-21-mercapcapto-16a,17- dimethyl to-16a-17-dimethy1magma-1,4- pregna-l,diene-3,2Udione, diene-3,20-dione. 21-acetate.

113. 9-tluoro-115,17-dihydroxy-21-9-fluoro-11B,17-dihydroxy-Zlmercapto-lo-methyleuemercapto-16-methylenepregnapregna-lA-dieneBflO-dione-1,4-diene-3,2D-dione. 2l-acetate.

114. 9-iluoro-11B-hydroxy-21-mer- 9fluoro11Bhydroxy-21-mercapto-2'-methyl]pregna-l,4- capto-2'methyl regna-1,4dieno[17a,16-d oxazolet", dieno[17a,16a-dYoxaz0le-3,20-3,20-dione,21-acetate. dione.

115-.- 9-fiuoro-11B,16a,17-trihydroxy- 9-fluoro-11B,16a,17-trihydroxy-21-mercapto pregna-IA- zl-mereapto pregna-lA diene diene-3,20-dione,3,20-dioue. 21-acetate.

EXAMPLES 116-120 Following the procedure of Example 98 but substitutingthe acylthio steroids indicated below for 9a-flouro-11p,16a,17-trihydroxy 21 cyclic 16,17-aceta1 with acetone in 3,20-dione,ZI-acetate,

mercaptopregna-l,4-diene- Example 98 gives the title compound.

Example: Column I 116 9-fluoro 11B,16a,17 trihydroxy-21- mercaptopregna1,4-diene 3,20-

dione 21 hexanoate,

cyclic 16,17-

acetal with acetone. 117 9-fluoro 11p,16u,17trihydroxy-Zlmercaptoprcgna-1,4 diene 3,20-

dione,

21-benzoate,

cyclic 16,17-

acetal with acetone.

118 9-fluoro-11p,16a,17

trihydroxy 21- mercaptopregna-1,4 diene 3,20- dione, 2l-(pchlorobcnzoate), cyclic 16,17-acetal with acetone.

119 9-fl1l0tO-11fl,16a,17 trihydroxy 21- mercaptopregna-1,4 diene 3,20-dione, 21-(p-methoxybenzoate), cycyic 16,17-acetal with acetone.

120 9-fluoro-11fl,16a,17 trihydroxy 21- mercaptopregna 1,4 diene 3,20-dione, ZI-(p-methylbcnzoate), cyclic 16,17-acetal with acetone.

19 EXAMPLE 121 9-fiuoro-1 15, 160:, 17trihydroxy-Z1-(methyithio)-pregna- 1,4-diene-3,20-dione, cyclic16,17-acetal with acetone 4.5 g. of9-fluoro-1118,160,17-trihydroxy-21-mercapto pregna-1,4-diene-3,20-dione,cyclic 16,17-acetal with acetone and 0.25 g. of sodium hydride in 300ml. of 1,2- dimethoxyethane is stirred for two hours at 50. To thereaction is then added, in a dropwise manner, 1.56 g. of methyl iodidein 25 ml. 1,2-dimethoxyethane. Stirring is continued at 50 C. for 2days. The solvent is evapo rated to give the crude product which isrecrystallized from an acetone-petroleum ether mixture.

EXAMPLES 122-13 8 Following the procedure of Example 121 butsubstituting the 21-mercapto steroids in Column I below for9a-fluoro-11f3,16a,17-trihydroxy-2l-mercaptopregnal,4-diene-3,20-dione,cyclic 16,17-acetal with acetone in Example 121, the correspondingZl-methylthio steroids indicated in Column II are obtained.

Column I1 Ex. Column I 3,20-dione, cyclic 16,17- 3,20-dione,cyclic16,17'acetal acetai with acetone. with acetone.

123... 9-fluoro-l1fl,16a,17-trihydroxy- 9-fluoro-11B,l6a,l7-trihydroxy-21-mercaptopregna-L4 2l-(methylthio)pregna-1,4 diene-3,20-dione, cyclicdiene-3,20-dione, cyclic 16,17- 16,17-acetai with acetoacetal withacetophenone (B- phenone (IS-methyl).

124.... 9 fiuorol1 3,16a,l7-trlhydroxy- 21-mercaptopregna-1,4-diene-3,20-dione, cyclic 16,17-acetal with acetaldehyde (wmethyl).

125 9-iluoro-1lB,l6a,l7-trihydroxy- 2l-mercaptopregna-L4-diene-3,20-dione, cyclic 16,17-acetal with cyelohexanone.

126.115,17-dihydroxy-2l-mercepto6,16-dimethyl-l,4,6,lpregnatetraene-3,20-dione.

127. 9-fiuoro-11B,17-dihydroxy-2lmercapto-ltiB-methylpregna-1,4-diene3,20-dione.

128- 9-iluoro-1lfi,17-dihydroxy-Zlmercapto-16a-methylpregna-1,4-diene4i,2(}dione.

129 6a,9-diiluoro-l1fi,17a-diliydroxy-2l-rnercapto-16amethylpregna-1,4diene- 3.20-dione.

130--- 60:,9-diil11010-1lB,16a,l7-tl'iilydroxy-21-n1ercapto pregna-1,4diene3,20dione, cyclic 16,17-acetal with acetone.

131 6a-ilnoro1lB-hydroxy-21mercapto-lfia-methylpregnal,4diene-3,20-dione.

tone.

133 116,16a-17-trihydroxy-2l-mercapto pregna-l,4-diene-3,20- dione,cyclic 16,17-acetal with acetone.

134.-. 115,17-dihydroxy-21-mercap to-lG-methylene pregna-1,4-diene-3,204iione.

135 9-iluoro-11B-hydroxy-2l-mercepto-16a,17-dimethylpregna-1,4diene-3,20-diore.

136 9-tluoro-11B,17-dihydroxy-21-mercaptolfi-methylenepregna-lA-diene-Bfltldione.

138 9-fiuoro-11B,16a,l7-trihydroxy- ZI-mereapto pregna-1,4. diene-3,20iione.

methyl). 9-fiuoro-11B,16a,17-trlhydroxy- 2l-(methylthio)pregna-1,4-diene'3,20-dione, cyclic 16,17- acetal with acetaldehyde (amethyl).

9-fiuoro-115J6a 17-trihydroxy- 21-(methylthio)pregna-1,4- diene-3,2O-dione, cyclic 16,17- acetal with cyclohexanone.

tone. 1m,16 x,17-trihydroxy-2l- (methylthio)pregna-1,4diene 3,2(Hiione,cyclic 16,17-acetal with acetone. 11B,17-dihydroxy-16-methylene-2l-(methy1thio)pregna-l,4 diene-3,20-dione. 9-iiuoro-11B-hydroxy-16a,17-dimethyl-21-(rncthylthie) pregna-lA-diene-iizwlione.9-fiuoro-11B,17-dihydroxy-16- methylene-Zl-(methylthio)pregna-lkdieneiiJO-dlone. Q-fiuoro-HB-hydroxy-Zl-(methylthio)-2-methylpregna-1,4'dieno[17a,16a-d]-oxazole-3,20-dione.9-fiuoro-11B,16u,17-trihydroxy 21-(methylthio)pregna-1,4- diene-3,201ione.

EXAMPLE 139 9-tluoro-l 1B, 16m,l7-trihydroxy-2l-iodopregna-4-ene-3 ,20-dione, cyclic 16,17-acetal with acetone To a rapidly stirred mixture of7.45 g. of 9-fiuoro-llfl, 16u,17-trihydr0xypregna-l,4-diene-3,20 dione,cyclic l6, l7-acetal with acetone, 9.90 g. of calcium oxide and 0.33 g.a,a'-azabisisobutyronitrile in 200 ml. tetrahydrQ l a 20 methanol (1:1),is added dropwise a solution of 6.6 g. iodine in 33 ml. tetrahydrofuranand 19 ml. methanol. The reaction is stirred for three hours, pouredinto methylene chloride and filtered. The filtrate is washed with 3%aqueous sodium thiosulfate, water and solvent evaporated at below 40 C.to give the title compound.

EXAMPLE 140 9-flu0ro-l 1B,l6a,17-trihydroxy-2l-iodopregna-1,4-diene-320-dione, cyclic 16,17-acetal with acetone To 3.21 g. of9-fiuoro-l15,160,17,2l-tetrahydroxypregna-l,4-diene-3,20dione,2-p-toluenesulfonate, cyclic 16,17-acetal with acetone in 35 ml. acetoneis added 2.88 g. of sodium iodide in 25 ml. acetone. The reaction isrefluxed for eight hours, evaporated to a volume of ca. 8 ml. andcooled. 10 ml. of 0.1 N sodium thiosulfate is added and the reaction iscooled to 0 C. The title compound is filtered oif and dried.

EXAMPLES 141-157 Following the procedure of Example 140 but substitutingthe steroid tosylates in Column I below for 9-fiuoro-11,8,l6u,17,2l-tetrahydroxypregna-1,4-diene 3,20 dione,2l-p-toluenesulfonate, cyclic 16,17-aceta1 with acetone in Example 140,the corresponding 21-iodo steroids in Column II are obtained:

Ex. Column I Column II 141.- 9-iluoro-11B, 16a, 17, 21- 9-fiuoro-11fl,16a, 17-trihydr0xytetrahydroxy-pregnai-ene 21-iodopregna-4-ene-3 20-ionate.

6a,9-diflu0r0-11B,16a,17,21- tetrahydroxypregna-L4- dlene-3,20-dione,21-ptoluenesulionate, cyclic 16,17-acetal with acetone.

sulionate.

9,11fl-dichloro-6B-fluorm 16a,17,21,trihydroxypregna-1,4diene-3,20-dione, 21-ptoluenesulfonate cyclic 16,

17-acetal with acetone.

11B,16a,17,21-tetrahydroxypregna-1,4-diene3,20-dione21-p-to1uenesulionate, cyclic 16,17-acetal with acetone.

3... 11B,17,21-trihydroxy-16- methylenepregna-lA-daene- 3,20'dlone,21-p-toluenesulionate.

154 9-fluoro-1lB,21-dihydroxy- 16a,17-dimethylpregna-1,4-diene-3,20-dione, 21-ptoluenesulionate.

155 9-fluoro-113,17,21-trihydroxyl6-methylenepregna-1,4-diene43,20-dione, 21-ptoluenesulionate,

dioue, cyclic-16,17-acetal with with acetone.

21-iodopregna-1,4-diene-3, dione, cyclic 16,17-acetal with ecetophenonci-methyl).

9-fluoro-1lB,l6a, 17-trihydroxy- 21-iodopregna-L4 dime-3,20- dlone,cyclic 16,17-acetal with acetal-dehyde (amethyl).

21-iodopregna-1,4 diene-3,20- dione, cyclic 16,17-acetal withcyclohexanone.

115,17-dihydroxy-21-iodo-6,

lfi-dimethyl-l,4,6,15-pregnatetraene-B, one.

6a,9-difluoro-11B 1641,17-

trihydroxy-2lodopregna-1,4- diene-3,20-dione, cyclic 16,17- acetal withacetone.

9,11B-dichlorofiB-fluoro-16a,

17-dihydroxy-2i'iodopregna- 1,4-diene'3,20-dione, cyclic 16,17-acetalwith acetone.

11fl,16a,17-trihydroxy-21- iodopregna-1,4-d1cne-3,2D- dionc, cyclic16,17-acetal with acetone.

11 3,17-dihydroxy-21-iodo:16

methylenepregna-l,-diene- 3,20-dione.

EXAMPLE 158 9-fluoro-1 1B,l6a,17-trihydroxy-2-mercaptopregna-l ,4-diene-'3,20-dione, cyclic 16,17-acetal with acetone Method A: A solutioncontaining 5.9 g. of sodium ethoxide in 100 ml. of dimethylformamide issaturated with dry hydrogen sulfide. To this solution is added 14.7 g.of 9-fluoro-l15,16u,17,2l-tetrahyrdoxypyregna-l,4-diene-3,20-dione,21-p-toluenesulf0nate, cyclic 11,17-acetul with acetone in 50 ml. ofdimethylformamide. After heating for 12 hours at 100, the reaction isconcentrated to a volume of ca. 30 ml., cooled, treated with 7.25 ml.concentrated hydrochloric acid and poured into 90 ml. of water. Thetitle compound is filtered off and dried.

Method B: Following the procedure of Method A, but substituting9-fluoro-l1p,16a,17-trihydroxy 21 iodopregna-l,4-diene-3,20-dione,cyclic 16,17-acetal with acetone for9-fluoro-115,160,17,ZI-tertahydroxypregna-IA diene-3,20-dione, 21-ptoluenesulfonate, cyclic 16,17- acetal with acetone in Method A, givesthe title compound.

What is claimed is:

1. A compound having the structure wherein R is lower alkyl of 1 to 6carbon atoms, cyclm alkyl of 3 to 7 carbon atoms, monocarbocyclic aryl,or monocarbocyclic aralkyl; R is hydrogen, lower alkyl of 1 to 6 carbonatoms, or hydroxy; R is hydrogen, lower alkyl of 1 to 6 carbon atoms,methylene, or hydroxy; or R and R may together form a cyclized dioxologroup of the structure R; or a cyclized oxazole group of the structureN=CRo 22 3. A method of preparing a compound having the structure:

wherein R is lower alkyl of l to 6 carbon atoms, cycloalkyl of 3 to 7carbon atoms, monocarbocyclic aryl, or monocarbocyclic aralkyl; R ishydrogen, lower alkyl of 1 to 6 carbon atoms, or hydroxy; R is hydrogen,lower alkyl of 1 to 6 carbon atoms, methylene, or hydroxy; or R and Rmay together form a cyclized dioxolo group of the structure --0 R5 or acyclized oxazole group of the structure N=C--Rt wherein R and R are thesame or difierent and are hydrogen, lower alkyl of 1 to 6 carbon atomsor monocarbocyclic aryl or R and R together form a cycloalkyl group of 3to 7 carbon atoms and wherein R is lower alkyl of 1 t0 6 carbon atoms;X, is hydroxy or halogen; X is hydrogen or halogen; and X is hydrogen,lower alkyl of 1 to 6 carbon atoms or halogen, which comprises reactinga compound having the structure:

according to claim 4 wherein the halo 1 wherein the preg' ReferencesCited UNITED STATES PATENTS 3,681,407 8/1972 Los 260-3974 HENRY A.FRENCH, Primary Examiner US. Cl. X.R.

Patent I30.

Dated April 9, 1974 Inventor(s) B. Richard Vogt It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 2,

Column 4,

Column Column Column 14,

Column 16,

Column 15,

line 28, the word "leu" should he: lieu formula II, lines 21 through 34and formula II, lines 45 through 58, that portion of the formulareading:

" l Iv S--R should be: .R 3 R line 23, delete the word "could" andinsert the word: cold should be:

line 55, the word "procedurde" should be:

- procedure line 40, Example 81, Column I, insert a hyphen after theword "methylpregna".

line-54, Example 69, Column II, the word "dlene" should be: diene PatentNO. I

Inventor(s) Dated April 9, 1974 B. Richard Vogt It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column Column Column Column Column Column Column Column Column ColumnColumn Column Example 85, Column I, that portion reading:

line 53,

should be: cyclic l6,l7-

"cyclic 16,27-

line 63, Example 89, Column II, that portion reading: "ercapto" shouldbe: mercapto Example 90, Column I, that portion-reading:

should be: l,4dieneline 65, "l,4dione-" Column I, after the words:

line l9,Example 107,

-- 2l-acetate, cyclic "3,20-dione" insert:

line 18, Example 107, Column II, the word reading: "pergna-" should be:pregnaline 6, "0.25 9]" should be: 0.24 g

line 59, Example ;l3 5, Column I, the word "diore" should be: dione line53, Example 148, Column II, the word "methylprenga-" should be:methylpregna Column 1, that portion reading:

l,4diene line 60, Example 150, "l4,diene-" should be:

line 70, Example 154, Column II, delete the colon (z) and insert in itsplace a hyphen line 18, tetrahyrdoxypyregnashould be:

-- tetrahydroxypregna line 19, "ll,l7-acetal" should be: l6,l7acetal mg?UNITED STATES PA'l'tLLi'l' Ur'ilbb CERTIFICATE OF CORRECTION 3, 803,133-Dated April 9, 1974 Patent Flo lnvcntor( Rlchard Vogt;

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

' '1 Column 21, Claim 1, that portion of the structure, lines 39 to 43,reading:

S AT 3 should be:

Column 21, Claim 1, line 65, the word "cabon" should be:

carbon Column 21, Claim 1, line 68, delete the comma at the end of theline.

Signed and sealed this 17th day of September 1974.

(SEAL) Attest: McCOY M. GIBSON JR. C. MARSHALL DANN Attesting OfficerCommissioner of Patents

